Although
epidermal growth factor receptor (EGFR) inhibitors are a mainstay for
treating lung cancers, the drugs are limited by primary or acquired drug
resistance that can arise through multiple molecular mechanisms.2-4

To
better understand the mediators of that resistance, the Sinai-Case Western
group focused on two tumor suppressors: Kruppel-like factor 6 (KLF6; COPEB; ZF9) and forkhead box O1 (FOXO1). Prior studies showed that KLF6
levels are lower in lung adenocarcinomas than in matched normal lung tissue.

FOXO1 is the direct transcriptional activator of KLF6 and
is inactivated in cancers. The inactivation occurs when FOXO1 is sequestered in
the cytoplasm instead of the nucleus where it normally localizes.5,6

In
mice with EGFR-activated lung adenocarcinoma, the EGFR inhibitor Tarceva erlotinib induced apoptosis
and increased levels of KLF6 compared with those in control animals. Moreover,
in human EGFR-activated lung adenocarcinoma cell lines that were sensitive to
Tarceva, cells given the drug showed greater levels of KLF6, nuclear
accumulation of FOXO1 and apoptosis than untreated cells.

By
contrast, human EGFR-activated lung adenocarcinoma cell lines that were Tarceva
resistant did not undergo apoptosis, had no KLF6 activation and had FOXO1 that
remained in the cytoplasm.

In
the Tarceva-sensitive cell lines, small interfering RNA targeting FOXO1 or KLF6
prevented drug-mediated apoptosis, suggesting FOXO1 and KLF6 are necessary for
Tarceva-mediated apoptosis and sensitivity to anti-EGFR therapy.

The
next step was to try to re-establish sensitivity to Tarceva by enhancing the
nuclear accumulation of FOXO1 and the subsequent upregulation of KLF6.

To
do so, the researchers turned to trifluoperazine, which is approved as an
antipsychotic and antiemetic. The drug had been tried in cancer trials in
combination with chemotherapy because trifluoperazine has off-target activity
on the p-glycoprotein drug
resistance pump, although none of the studies bore fruit.7-10

The
findings could help explain the biology underlying prior observations that both
schizophrenic patients receiving dopamine receptor antagonists and
dopaminergic-deficient Parkinson's disease patients have a lower incidence of
some cancers than the general population.12,13

According to Goutham Narla, Mount Sinai and
Case Western team leader and assistant professor of medicine and transformative
molecular medicine at Case Western, "Our combination of trifluoperazine
and erlotinib resulted in a successful therapeutic strategy because the
combination provides a marked synergy due to a known mechanism of action-nuclear
accumulation of FOXO1 and increased expression of KLF6."

Narla
thinks it would be a good idea to "go back and screen other FDA-approved
drugs of this class to see if they could be resurrected to treat anti-EGFR-resistant
cancers."

Because
dopamine receptors are a subclass of G
protein-coupled receptors (GPCRs), Narla said the
repurposing search could be far-reaching.

"Compounds
that target dopamine receptors or GPCRs might also affect the nuclear
accumulation of FOXO1 or other downstream mediators of EGFR signaling, which
would have before been considered off-target activity considering their
original purpose," he said.

He
added, "Drugs that are just sitting on the shelf because they had shown a
suboptimal profile as GPCR antagonists could be rescreened as anticancer
therapeutics. We have been using cancer cell viability assays to reevaluate
GPCR antagonists as anticancer agents" but want to take a step forward and
incorporate a new assay being developed by Mick Bhatia (seeBox 1, "Honing in on differentiation").

In
addition to looking for repurposing opportunities, the group is synthesizing
analogs of trifluoperazine. The molecule's "backbone is a rich scaffold
that can be derivatized to provide us a compound with improved pharmacology,
particularly with respect to CNS effects," noted Narla. "Michael
Ohlmeyer will be leading the medicinal chemistry aspect of the project, and his
team was a recipient of the 2012 NYCIF BioAccelerate prize for this work."
The $250,000 award for one year is intended to fund biomedical research with
commercial promise.

Ohlmeyer
is an associate professor of structural and chemical biology at the Mount Sinai
School of Medicine. He cofounded chemistry company Pharmacopeia Inc., now Accelrys Inc., and is an author on the JCI paper.

Other
next steps include clinical trials and testing the combination of trifluoperazine
with other EGFR-targeting therapies in other cancers.

Mount
Sinai has filed a patent application covering the work, which is available for
licensing.

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